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Brazil nuts are a very good source of selenium. Fish, shellfish, red meat, grains, eggs, chicken, liver, and garlic are also good sources. Meats produced from animals that ate grains or plants found in selenium-rich soil have higher levels of selenium.
Keshan disease is caused by a lack of selenium. This leads to an abnormality of the heart muscle. Keshan disease caused many childhood deaths in China until the link to selenium was discovered and supplements were given.
Too much selenium in the blood can cause a condition called selenosis. Selenosis can cause hair loss, nail problems, nausea, irritability, fatigue, and mild nerve damage. However, selenium toxicity is rare in the United States.
Dosages for selenium, as well as other nutrients, are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board at the National Academies of Sciences, Engineering, and Medicine. DRI is a term for a set of reference intakes that are used to plan and assess the nutrient intakes of healthy people.
Selenium (Se) is an essential trace element in humans1,2. Selenium is generally taken up from the diet through food or other forms of external supplementation. Dietary selenium is obtained in the form of selenomethionine (SeMet), selenocysteine (Sec), selenite, and selenate. Significant health benefits have been attributed to selenium metabolic systems that play major physiological roles in thyroid hormone metabolism, immunity, and antioxidant defense2,3. Selenium is required for the production of thyroid hormone-metabolizing enzymes and selenium supplementation is thought to improve the function of thyrocytes and immune cells4. Selenium supplementation demonstrated immunostimulant effects, such as enhanced proliferation of activated T cells, activation of natural killer cells, and tumor cytotoxicity mediated by cytotoxic lymphocytes5,6. In contrast, selenium deficiency is associated with the occurrence, virulence, and disease progression of viral infections7.
OA is characterized by progressive loss of cartilage extracellular matrix (ECM) and pathological changes in other joint tissues such as subchondral bone sclerosis, osteophyte formation, and synovial inflammation31. Cartilage destruction is considered a hallmark of OA and is a result of increased production of catabolic effectors32,33,34,35 and reduced matrix biosynthesis by chondrocytes36. OA is associated with multiple etiologies involving systemic factors such as age37 as well as local factors such as mechanical stress38 driven by weight-bearing and joint instability. Both OA-causing factors have been found to cause oxidative stress in chondrocytes. Oxidative stress results from the abnormal production of reactive oxygen species (ROS) and the loss of cellular antioxidant capacity. Many preclinical and clinical studies have indicated the accumulation of oxidative burden in chondrocytes undergoing osteoarthritic changes39,40. Emerging evidence suggests that oxidative stress is mechanistically linked to the initiation of osteoarthritic changes in chondrocytes through the acquisition of senescent phenotypes36. Therefore, restoring redox homeostasis can serve as a rational therapeutic strategy to alleviate OA progression. Here, we review the role of selenium metabolism in cartilage and bone and the significance of maintaining its homeostasis in the context of joint diseases such as KBD and OA.
Selenoprotein is defined as a protein containing Sec amino acid residue. The biological functions of selenium are mostly exerted through selenoprotein domains that contain Sec residues. Twenty-five selenoprotein genes have been identified in the human genome45. In mice, a total of 24 selenoproteins have been characterized46 and targeted deletion of some of these selenoproteins demonstrated their essential roles in developmental processes and in disease pathogenesis. Selenoproteins can be classified into subfamilies based on their cellular functions such as those implicated in antioxidation (GPX1, GPX2, GPX3, GPX4), redox regulation (TXNRD1, TXNRD2, TXNRD3, MSRB1, SELENOH, SELENOM, SELENOW), thyroid hormone metabolism (DIO1, DIO2, DIO3), selenium transport and storage (SELENOP), selenophosphate synthesis (SEPHS2), calcium metabolism (SELENOK, SELENOT), myogenesis (SELENON), protein folding (SELENOF, SELENOI, SELENOS), and protein AMPylation (SELENOO)47,48. The functions of other selenoproteins such as GPX6 and SELENOV still remain unclear. Glutathione peroxidases (GPXs) such as GPX1 (cytosolic GPX), GPX2 (gastrointestinal GPX), and GPX4 (phospholipid hydroperoxide GPX) catalyze the decomposition of a great variety of peroxides, thus protecting cells against oxidative damage49,50. Thioredoxin reductases (TXNRDs) employ NADPH as an electron donor to revert oxidized TXN to a reduced dithiol, the oxidation status of which is critically implicated in regulating various cell behaviors including proliferation and apoptosis51. The physiological significance of TXNRDs is further supported by the embryonic lethality of Txnrd1 or Txnrd2 knockout mice52,53. Deiodinases (DIOs) regulate thyroid hormone metabolism by catalyzing the conversion of thyroid hormones from precursor thyroxine (T4) to biologically active triiodothyronine (T3) or inactive reverse T3 (rT3)54. The expression levels of several selenoproteins are influenced by the extent of selenium uptake. For example, selenium-deficient animals and human cell lines exhibit reduced transcription of selenoproteins such as GPX1, DIOs, SELENOI, and SELENOW55,56,57. A subset of selenoproteins such as GPX1 and SELENOW is more sensitive to selenium supplementation or deficiency. The hierarchy of selenoprotein expression is more apparent when the intracellular level of selenium is limited1.
Selenium-responsive genes are the genes whose expression patterns are influenced by supplementation with selenium or selenium-containing compounds. Treatment of a cancer cell line with methylseleninic acid induced expression changes in 951 genes58. These responsive genes were closely associated with annotations related to cell cycle regulation, androgen-responsive genes, and phase II detoxification pathway. Selenium supplementation of macrophages diminished the expression of lipopolysaccharide (LPS)-induced pro-inflammatory genes such as cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α)59, suggesting that selenium has anti-inflammatory effects on the immune system. The CTD database ( ) reports the effect of environmental chemicals including selenium on gene expression profiles in various human tissues.
Joints are composed of various types of connective tissues including cartilage, bone, synovium, meniscus, and ligament. Among these tissues, cartilage is the main component that absorbs mechanical stress, cushioning bones from impacting each other during various weight-bearing activities. In the human knee joint, the selenium concentration in cartilage is approximately 80 μg/kg dry weight, whereas the selenium concentrations in ligament and meniscus are 270 and 307 μg/kg dry weight, respectively60,61. The requirement of adequate physiological selenium levels for maintaining cartilage homeostasis has been recognized. Selenium deficiency retards the growth and development of cartilage and bone62,63,64,65,66. Growth retardation was observed in rats after two generations of selenium deficiency62. Mice fed a diet deficient in selenium resulted in fibrocartilage formation at the articular surface, ultimately showing degeneration of articular cartilage63. Selenium deficiency induced the expression of the chondrocyte hypertrophy marker gene type X collagen (COLX) in articular cartilage64. The expression of parathyroid hormone-related protein (PTHrP), which controls chondrocyte maturation during endochondral ossification, was enhanced in both articular cartilage and hypertrophic growth plate following selenium deficiency. These changes were in line with the phenotypic changes observed in the cartilage of KBD patients64. However, it should be noted that growth retardation caused by selenium deficiency may also be associated with the deregulation of bone metabolism65. In a study by Cao et al., selenium deficiency severely compromised bone microarchitecture as a result of increased bone resorption66.
Selenium deficiency is regarded as one of the initiating factors of KBD, which is an endemic osteoarthropathy caused by the premature closure of epiphyseal plate and the impaired skeletal development. Skeletal deformities in hands, fingers, knees, and elbows, and in severe cases, dwarfism and movement disorders are the symptoms of KBD22. The KBD area roughly coincides with low-selenium areas including a geological belt extending from northeast to southwest China, North Korea, and eastern Siberia22. A meta-analysis showed that selenium levels in the water, soil, cereal, and corn in KBD endemic regions were lower than they were in non-endemic regions, supporting the fact that the level of selenium in tissue is predominantly affected by dietary intake23. In line with this finding, selenium levels in the whole blood, serum, hair, and urine of KBD patients were markedly lower than those of healthy controls24.
The animals fed a selenium-deficient diet recapitulated some of the pathological manifestations of KBD, strongly supporting the notion that selenium deficiency is critically associated with the development of this endemic arthropathy. Selenium deficiency impaired bone and cartilage growth with the exhibition of premature chondrocyte hypertrophy as evidenced by an increased expression of COLX, compatible with the phenotypes in KBD cartilage64. The low-selenium condition in combination with three mycotoxins, deoxynivalenol (DON), nivalenol (NIV), and T-2, yielded pro-catabolic changes and hypertrophic phenotype of chondrocytes, as evidenced by the loss of aggrecan and type II collagen (COLII) and the increase in COLX and matrix metalloproteinases (MMPs) expression, respectively71. In contrast, selenium supplementation partially alleviated these mycotoxin-induced damages in chondrocytes71. In rats, dietary selenium deficiency over two generations caused the onset of physiological selenium insufficiency72. In this condition, pathological changes in the epiphyseal plate were observed with the decreased expression of COLII and GPX1 in the chondrocytes, suggesting a possible association of reduced chondrocyte anabolism and antioxidant capacity with the epiphyseal plate lesions observed in KBD72. The relevance of impaired selenium metabolism to the onset of KBD was further validated using a mouse genetic deletion model. Targeted deletion of Sec-tRNA[Ser]Sec (Trsp) gene in osteochondroprogenitor cells from embryonic stage caused the depletion of selenoproteins in skeletal systems, causing growth retardation, abnormalities in the epiphyseal growth plate, delayed endochondral ossification, and chondronecrosis, which recapitulated the major pathological features of KBD73.
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